1. Field of the Invention
The present invention relates to certain selected transient prodrug forms of progesterone and related compounds useful in the treatment of acne and seborrhea.
For purposes of this specification, the term "prodrug" denotes a derivative of a known and proven prior art steroid compound [i.e., progesterone or a related compound] which derivative, when administered to a warm-blooded animal, "cleaves" in such a manner as to release the proven drug at its target site or sites of activity.
The term "transient" denotes enzymatic and/or chemical hydrolytic "cleavage" of the compounds of the instant invention in a manner such that the proven drug form [e.g., progesterone] is released, while the remaining "cleaved" moiety remains nontoxic and is metabolized in such a manner that nontoxic, metabolic products are produced.
Finally, the term "pharmaceutically acceptable acid addition salt" as used herein generally includes the nontoxic acid addition salts of selected compounds of formula [I], formed with nontoxic inorganic or organic acids. For example, the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycollic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, fumaric, sulfonic, toluenesulfonic, and the like.
2. Description of the Prior Art
Acne is a common disorder of the skin, especially prevalent during adolescence, characterized by the accumulation of sebum in the sebaceous ducts resulting from obstruction of the ducts and increased secretion of sebum. Studies have indicated that 5.alpha.-dihydrotestosterone (5.alpha.-DHT) a metabolite of testosterone, stimulates the sebaceous glands, and is found in the skin of acne patients in much greater amounts than in normal skin. Thus, a substance able to inhibit 5.alpha.-reductase would presumably prevent the 5.alpha.-reduction of testosterone to 5.alpha.-DHT and resultant stimulation of the sebaceous glands.
Progesterone, a 5.alpha.-reductase inhibitor, has recently been found to be effective in the topical treatment of acne cases, especially in cases in which hypersecretion of the sebaceous gland is the dominant factor. [Drug Intelligence and Clinical Pharmacy, Volume 12, March, 1978, pp. 151-7.] However, progesterone suffers from a serious disadvantage in that it undergoes rapid metabolic deactivation after topical administration. Thus, very large doses of progesterone must be administered to provoke a response and the duration of activity is nevertheless quite short.
In view of the foregoing, it is apparent that a serious need exists for a class of novel progestins which will overcome the aforementioned inefficiencies. That need is fulfilled by the subject steroidal prodrugs which are topically active and are not rapidly metabolically deactivated, but which are transient and which will cleave upon administration to the active parent steroid resulting in therapeutic concentrations and eliciting, albeit more efficiently and prolongedly, the same pharmacodynamic effect as would be elicited upon administration of the known parent natural or synthetic progestin.